There is a strong positive association between cigarette smoking and alcohol use. It is estimated that approximately 20-25% of current smokers are also heavy drinkers. Greater alcohol use is associated with decreased odds of smoking cessation and it is estimated that smokers are 4 times more likely to experience a smoking lapse during drinking episodes. Despite these data, there are no available treatments tailored to heavy drinking smokers, a sizeable and treatment-resistant sub-group. This proposal seeks to address this gap in the literature by conducting a double-blind, randomized clinical trial using three group medication design consisting of VAR alone (1 mg twice daily), NTX alone ( 50 mg once daily), and the combination of VAR (1 mg twice daily) + NTX (50 mg once daily) for smoking cessation and alcohol use reduction in a sample of heavy drinking daily smokers (i.e., individuals who smoke = 10 cigarettes/day and who meet NIAAA guidelines for heavy drinking).The PI has recently completed a laboratory trial with non-treatment seeking heavy drinking which found that the combination of VAR + NTX was superior to monotherapy and to placebo in attenuating nicotine- and alcohol-induced reward during alcohol and cigarette administration in the lab. Further, the combination group significantly reduced cigarette and alcohol consumption during the active medication period, as compared to placebo. Based on the preliminary evidence from our human laboratory trial, this proposal extends these findings to treatment seeking populations by testing the combination of VAR and NTX for smoking cessation among heavy drinking smokers. A total of 411 treatment-seeking heavy drinking smokers will be randomized to (1) VAR only, (2) NTX only, or (3) VAR + NTX. Medication will be titrated over a 14-day period and all participants will receive individual counseling for smoking and drinking and will complete the laboratory testing session prior to the quit day. Smoking abstinence, verified by carbon monoxide (CO) levels and alcohol consumption will be measured at 2, 8, 12, 16, and 26 weeks after quit date. This study will test whether VAR + NTX result in higher rates of point prevalence smoking abstinence at 2, 8, 12, 16, and 26 weeks compared to monotherapy. It will also examine the effects of medication on alcohol use. The secondary aims are to test mechanisms of pharmacotherapy response by examining laboratory markers of nicotine and alcohol response as predictors of treatment outcome. Building upon our previous work, these aims will elucidate the combination of VAR + NTX is superior to monotherapy for alcohol use and smoking cessation in heavy drinking smokers.